Direct Regioselective para-Fluorination via I(I)/I(III) Catalysis

Fluorine scanning is an expansive strategy to refine the physicochemical profile of clinically important small molecule drugs. Of the possible regioisomers derived from mono-substituted benzenes, the para-fluorophenyl motif has emerged as a conspicuous chemotype: Lipitor is a compelling exemplar. When considered through this molecular design lens, the development of effective routes to generate this privileged module, without substrate pre-functionalization, remains very much in focus. Herein, we report a direct, para-selective fluorination that operates under the auspices of I(I)/I(III) catalysis. This enabling strategy leverages the venerable Leonard link inherent to phenylpropanoate and phenylpropanamides to promote a spirocyclization/para-selective activation sequence. Aside from biasing regioselectivity, the C₃-side chain of the Leonard link maps onto a range of common drug scaffolds and allows the substrate scope to be extended to amino acids and dipeptides (up to 94% yield). X-ray crystallographic analyses of selected products reveal intermolecular Dunitz-Diederich-type interactions between the C(sp²)-F bond and the π*_C═O orbital of proximal amides. It is envisaged that this organocatalytic platform to enable direct para-fluorination will facilitate the exploration of organo-fluorine chemical space.